Abstract

Alterations in ubiquitination and deubiquitination reactions have been directly implicated in the etiology of many malignancies. In general, specific cancers can result from stabilization of oncoproteins or destabilization of tumor suppressor genes. Proteasome inhibitors (PIs) represent potential novel anticancer therapy. These agents inhibit the degradation of multi-ubiquitinated target proteins, that is, cell cycle regulatory proteins such as cyclins and cyclin-dependent kinase inhibitors  that regulate cell cycle progression. Following the successful application of Bortezomib as an effective treatment for multiple myeloma (MM), a number of next-generation proteasome inhibitors have been developed with the goals of improving efficacy, overcoming drug resistance, minimizing dose-limiting toxicity such as peripheral neuropathy (PN), and improving convenience of administration. The recent accelerated approval of carfilzomib exemplifies the success of this approach, with other four inhibitors currently under study both preclinically and clinically. The role of PIs in hepatocellular carcinoma (HCC) has been demonstrated for the first time in 2004 that MG-132 induced apoptosis in human HCC cells through caspase-dependent cleavage of β-catenin and inhibition of β-catenin-mediated trans-activation. In addition, effect of Bortezomib on HCC was investigated and concluded that Bortezomib induced apoptosis in HepG2 cells as a model of HCC by stimulating both the extrinsic and intrinsic apoptotic pathways. Moreover, it has been shown that treatment with MG132 in combination with celecoxib resulted in synergistic anti-proliferative rather than anti-inflammatory and proapoptotic effects against liver cancer cells, providing a rational basis for the clinical use of this combination in the treatment of liver cancer.

Key words: Hepatocellular carcinoma, ubiquitin-proteasome pathway, proteasome inhibitors.